Objective: To evaluate the clinical correlates of and types of naturalistic treatments associated with sustained improvement/remission for at least 6 months in outpatients with bipolar disorder.

Method: Five hundred twenty-five outpatients with bipolar disorder (77.7% bipolar I) gave informed consent, had their mood rated daily on the National Institute of Mental Health Life Chart Method for a minimum of at least 1 year, and recorded all medications. Demographics and clinical characteristics of patients with a “sustained response” (ratings of “improved” or “very much improved” on the Clinical Global Impressions-Bipolar Version for a period of at least 6 months) versus nonresponders were compared. The study was conducted from 1996 to 2002.

Results: Of the 429 patients who were ill at study entry, 195 (45.5%) showed a sustained response; 54.5% showed no or insufficient response. A mean of 2.98 medications was given at time of improvement, which occurred after a mean of 18 months of participation in the study. Lithium and valproate were the medications most frequently prescribed at the time of improvement and had among the highest overall success rates. Equally complex regimens were employed in the nonresponders who, however, had a more adverse clinical course prior to network entry. Nonresponders were ultimately exposed to more antidepressants and antipsychotics than the sustained responders.

Conclusions: A mean of 1.5 years and at times highly complex medication regimens were required to achieve a sustained response for 6 months during naturalistic outpatient treatment of bipolar disorder. Delineating the clinical and biologic correlates of individual response to combination treatment is a very high clinical research priority, as is developing new treatment strategies for the large proportion of patients who fail to respond in a sustained fashion.